Bexagliflozin for Type 2 diabetes

INDICATIONS AND USAGE Bexagliflozin is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Limitations of Use Bexagliflozin is not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. [see Warnings and Precautions ( 5.1 )] . Bexagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. ( 1 ) Limitation of Use: Not recommended for use to improve glycemic control in patients with type 1 diabetes mellitus. ( 1 )

DOSAGE AND ADMINISTRATION • Recommended dose: 20 mg once daily, taken in the morning, with or without food. Do not crush or chew the tablet. ( 2.2 ) • Assess renal function before initiating bexagliflozin tablets and as clinically indicated. Correct volume depletion before initiating ( 2.1 ) • Not recommended if eGFR less than 30 mL/min/1.73 m 2 . ( 2.1 ) • Withhold bexagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting ( 2.3 ). 2.1 Testing Prior to Initiation and During Treatment with Bexagliflozin Tablets • Assess renal function prior to initiation of bexagliflozin tablets and periodically thereafter as clinically indicated [see Warnings and Precautions ( 5.3 )] . Bexagliflozin is not recommended in patients with an eGFR less than 30 mL/min/1.73 m 2 • Assess volume status. In patients with volume depletion, correct this condition before initiating bexagliflozin tablets [see Warnings and Precautions ( 5.3 ), Use in Specific Populations ( 8.5 , 8.6 )]. 2.2 Recommended Dosage • The recommended dosage of bexagliflozin tablets is 20 mg orally taken once daily in the morning, with or without food [see Clinical Pharmacology ( 12.3 )] . • Do not crush or chew the tablet. • If a dose is missed, take the missed dose as soon as possible. Do not double the next dose. 2.3 Temporary Interruption for Surgery • Withhold bexagliflozin tablets for at least 3 days, if possible, prior to major surgery or procedures associated with prolonged fasting. Resume bexagliflozin tablets when the patient is clinically stable and has resumed oral intake [see Warnings and Precautions ( 5.1 ) and Clinical Pharmacology ( 12.2 )] .

WARNINGS AND PRECAUTIONS Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis: Consider ketone monitoring in patients at risk for ketoacidosis, as indicated. Assess for ketoacidosis regardless of presenting blood glucose levels and discontinue bexagliflozin tablets if ketoacidosis is suspected. Monitor patients for resolution of ketoacidosis before restarting. ( 5.1 ) Lower limb amputation: Consider factors that may increase the risk for amputations before initiating bexagliflozin tablets. Monitor patients for signs and symptoms of infection, or ulcers of the lower limbs, and discontinue if these occur ( 5.2 ) . Volume depletion: May result in acute kidney injury. Before initiating bexagliflozin tablets, assess and correct volume status in patients with impaired renal function or low systolic blood pressure, elderly patients or patients on diuretics. Monitor for signs and symptoms during therapy ( 5.3 ) Urosepsis and pyelonephritis: Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated. ( 5.4 ) Hypoglycemia: Consider a lower dose of insulin or insulin secretagogue to reduce risk of hypoglycemia when used in combination with bexagliflozin tablets ( 5.5 ) Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene): Serious, life-threatening cases have occurred in both females and males treated with SGLT2 inhibitors. Assess patients presenting with pain or tenderness, erythema, or swelling in the genital or perineal area, along with fever or malaise. If suspected, institute prompt treatment ( 5.6 ). Genital mycotic infection: Monitor and treat as appropriate. ( 5.7 ) 5.1 Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis In patients with type 1 diabetes mellitus, bexagliflozin tablets significantly increase the risk of diabetic ketoacidosis, a life-threatening event, beyond background rate. In placebo-controlled trials of patients with type 1 diabetes mellitus, the risk of ketoacidosis was markedly increased in patients who received sodium glucose transporter 2 (SGLT2) inhibitors compared to patients who received placebo. Bexagliflozin tablets are not indicated for glycemic control in patients with type 1 diabetes mellitus. Type 2 diabetes mellitus and pancreatic disorders (e.g., history of pancreatitis or pancreatic surgery) are also risk factors for ketoacidosis. There have been postmarketing reports of fatal events of ketoacidosis in patients with type 2 diabetes mellitus using SGLT2 inhibitors. Precipitating conditions for diabetic ketoacidosis or other ketoacidosis include under-insulinization due to insulin dose reduction or missed insulin doses, acute febrile illness, reduced caloric intake, ketogenic diet, surgery, volume depletion, and alcohol abuse. Signs and symptoms are consistent with dehydration and severe metabolic acidosis and include nausea, vomiting, abdominal pain, generalized malaise, and shortness of breath. Blood glucose levels at presentation may be below those typically expected for diabetic ketoacidosis (e.g., less than 250 mg/dL). Ketoacidosis and glucosuria may persist longer than typically expected. Urinary glucose excretion persists for 3 days after discontinuing bexagliflozin tablets [see Clinical Pharmacology ( 12.2 )] ; however, there have been postmarketing reports of ketoacidosis and/or glucosuria lasting greater than 6 days and some up to 2 weeks after discontinuation of SGLT2 inhibitors. Consider ketone monitoring in patients at risk for ketoacidosis if indicated by the clinical situation. Assess for ketoacidosis regardless of presenting blood glucose levels in patients who present with signs and symptoms consistent with severe metabolic acidosis. If ketoacidosis is suspected, discontinue bexagliflozin tablets, promptly evaluate, and treat ketoacidosis, if confirmed. Monitor patients for resolution of ketoacidosis before restarting bexagliflozin tablets. Withhold bexagliflozin tablets, if possible, in temporary clinical situations that could predispose patients to ketoacidosis. Resume bexagliflozin tablets when the patient is clinically stable and has resumed oral intake [see Dosage and Administration ( 2.3 )] . Educate all patients on the signs and symptoms of ketoacidosis and instruct patients to discontinue bexagliflozin tablets and seek medical attention immediately if signs and symptoms occur. 5.2 Lower Limb Amputation An increased incidence of lower limb amputations occurred in bexagliflozin-treated patients compared to placebo-treated patients (8.3 versus 5.1 events per 1,000 patient-years) in a randomized, placebo-controlled trial evaluating patients with type 2 diabetes who had either established cardiovascular disease (CVD) or were at risk for CVD (Trial 6). Additional amputation data from Trial 6 are shown in Table 2 [see Adverse Reactions ( 6.1 )]. Of the 23 bexagliflozin-treated patients who had amputations, 15 were amputations of the toe and midfoot and 8 were amputations above and below the knee. Some patients had multiple amputations. Lower limb infections, gangrene, ischemia, and osteomyelitis were the most common precipitating medical events leading to the need for an amputation. The risk of amputation was highest in patients with a baseline history of prior amputation, peripheral vascular disease, and neuropathy. Before initiating bexagliflozin tablets, consider factors in the patient history that may predispose to the need for amputations, such as a history of prior amputation, peripheral vascular disease, neuropathy and diabetic foot ulcers. Counsel patients about the importance of routine preventative foot care. Monitor patients receiving bexagliflozin tablets for signs and symptoms of infection (including osteomyelitis), new pain or tenderness, sores or ulcers involving the lower limbs, and discontinue bexagliflozin tablets if these complications occur. 5.3 Volume Depletion Bexagliflozin can cause intravascular volume contraction which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine [see Adverse Reactions ( 6.1 )] . There have been postmarketing reports of acute kidney injury, some requiring hospitalization and dialysis, in patients with type 2 diabetes mellitus receiving SGLT2 inhibitors. Patients with impaired renal function (eGFR less than 60 mL/min/1.73 m 2 ) [see Use in Specific Populations ( 8.6 )] , elderly patients, patients with low systolic blood pressure, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating bexagliflozin tablets in patients with one or more of these characteristics, assess volume status and renal function [see Dosage and Administration ( 2.1 )] . In patients with volume depletion, correct this condition before initiating bexagliflozin tablets. Monitor for signs and symptoms of volume depletion, and renal function after initiating therapy. 5.4 Urosepsis and Pyelonephritis There have been reports of serious urinary tract infections, including urosepsis and pyelonephritis, requiring hospitalization in patients receiving SGLT2 inhibitors, including bexagliflozin tablets. Treatment with SGLT2 inhibitors, including bexagliflozin tablets, increases the risk for urinary tract infections. Evaluate patients for signs and symptoms of urinary tract infections and treat promptly, if indicated [see Adverse Reactions ( 6.1 )] . 5.5 Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues Insulin and insulin secretagogues (e.g., sulfonylureas) are known to cause hypoglycemia. Bexagliflozin tablets may increase the risk of hypoglycemia when used in combination with insulin and/or an insulin secretagogue [see Adverse Reactions ( 6.1 )] . A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with bexagliflozin tablets. 5.6 Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) Re

DRUG INTERACTIONS See Table 4 for clinically significant interactions with bexagliflozin tablets. Table 4. Clinically Significant Interactions with Bexagliflozin Tablets UGT Enzyme Inducers Clinical Impact UGT Enzyme Inducers may significantly reduce exposure to bexagliflozin and lead to a decreased efficacy [ see Clinical Pharmacology ( 12.3 )]. Intervention Consider adding another antihyperglycemic agent in patients who require additional glycemic control. Concomitant Use with Insulin and Insulin Secretagogues Clinical Impact The risk of hypoglycemia is increased when bexagliflozin tablets are used in combination with insulin and/or an insulin secretagogue. Intervention A lower dose of insulin or insulin secretagogue may be required to minimize the risk of hypoglycemia when used in combination with bexagliflozin tablets. Lithium Clinical Impact Concomitant use with SGLT2 inhibitors such as bexagliflozin tablets may decrease serum lithium concentrations. Intervention Monitor serum lithium concentration more frequently upon bexagliflozin tablets initiation and discontinuation. Positive Urine Glucose Test Clinical Impact SGLT2 inhibitors increase urinary glucose excretion and will lead to positive urine glucose tests. Intervention Monitoring glycemic control with urine glucose tests is not recommended in patients taking SGLT2 inhibitors. Use alternative methods to monitor glycemic control. Interference with 1,5-anhydroglucitol (1,5-AG) Assay Clinical Impact Measurements of 1,5-AG are unreliable in assessing glycemic control in patients taking SGLT2 inhibitors. Intervention Monitoring glycemic control with 1,5-AG assay is not recommended. Use alternative methods to monitor glycemic control.

ADVERSE REACTIONS The following important adverse reactions are described below and elsewhere in the labeling: Diabetic Ketoacidosis in Patients with Type 1 Diabetes Mellitus and Other Ketoacidosis [see Warnings and Precautions ( 5.1 )] Lower Limb Amputation [see Warnings and Precautions ( 5.2 ) ] Volume Depletion [see Warnings and Precautions ( 5.3 )] Urosepsis and Pyelonephritis [see Warnings and Precautions ( 5.4 )] Hypoglycemia with Concomitant Use with Insulin and Insulin Secretagogues [see Warnings and Precautions ( 5.5 )] Necrotizing Fasciitis of the Perineum (Fournier’s Gangrene) [see Warnings and Precautions ( 5.6 )] Genital Mycotic Infections [see Warnings and Precautions ( 5.7 )] Most common adverse reactions (incidence > 5%) are female genital mycotic infections, urinary tract infection and increased urination ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact the bexagliflozin information line at 1-855-273-6928 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Pool of Placebo-Controlled Trials Evaluating Bexagliflozin Tablets, 20 m g The data in Table 1 are derived from three trials in adults with type 2 diabetes mellitus: two 24-week placebo-controlled trials (one as monotherapy and another as add-on to metformin therapy; Trials 1 and 2, respectively) [see Clinical Studies ( 14.2 , 14.3 )] and a 12-week, placebo-controlled, dose-ranging, monotherapy trial (only the data from the 20 mg dosage of bexagliflozin tablets per day were included in this pool). In these pooled trials, patients received placebo (N = 300) or bexagliflozin 20 mg (N = 372), once daily. The mean age of the population was 56 years and 5% of the patients were older than 75 years of age. Fifty-seven percent (57%) were male and 45% were White, 38% Asian, 15% Black and 2% other races. At baseline, the mean duration of type 2 diabetes mellitus was 7.7 years and the mean hemoglobin A1c (HbA1c) was 8.2%. Established microvascular complications of type 2 diabetes mellitus at baseline included diabetic nephropathy (0.8%), retinopathy (24%), and peripheral neuropathy (33%). Baseline renal function was eGFR ≥ 60 mL/min/1.73 m 2 in 98% of patients and eGFR 45 to < 60 mL/min/1.73 m 2 in 2% of patients (mean eGFR 92 mL/min/1.73 m 2 ). Table 1 shows common adverse reactions associated with the use of bexagliflozin tablets in these trials. These adverse reactions occurred more commonly in bexagliflozin-treated patients than placebo-treated patients, and occurred in at least 2% of bexagliflozin-treated patients. Table 1. Adverse Reactions in Adults with Type 2 Diabetes Mellitus - Monotherapy or in Combination with Metformin* Percentage of Patients Placebo N = 300 Bexagliflozin N = 372 Increased urination a 3 7 Urinary tract infection b 4 6 Female genital mycotic infections c 0 6 Thirst d 2 3 Vaginal pruritus e 0 3 Male genital mycotic infection f 1 2 Hypoglycemia 1 2 * The three placebo-controlled trials included two monotherapy trials and one add-on combination trial with metformin in adults with type 2 diabetes mellitus (Trials 1, 2, and a 12-week dose ranging trial). Adverse reactions were those that occurred more commonly in bexagliflozin-treated patients than placebo-treated patients and occurred in at least 2% of bexagliflozin-treated patients. a Includes: polyuria, pollakiuria, micturition urgency, nocturia. b Includes: dysuria, urinary tract infection, nitrite urine present, streptococcal urinary tract infection, cystitis. c Includes: vulvovaginal mycotic infection, vaginal infection, genital infection fungal, vulvovaginal candidiasis. Percentages calculated with the number of female patients in each group as denominator: placebo (N = 130), bexagliflozin tablets(N = 156). d Includes: thirst, polydipsia. e Includes: pruritus genital, vulvovaginal pruritus. Percentages calculated with the number of females in each group as denominator: placebo (N = 130), bexagliflozin tablets (N = 156). f Includes: balanoposthitis, genital infection fungal, tinea cruris. Percentages calculated with the number of males in each group as denominator: placebo (N = 170), bexagliflozin tablets (N = 216). Clinical Trial in Patients with Increased Risk for Major Adverse Cardiovascular Events Bexagliflozin tablets were evaluated in a trial that enrolled adults with type 2 diabetes mellitus who had either established (CVD) or were at increased risk for CVD (Trial 6) [see Clinical Studies ( 14.5 )] . Patients on standard of care therapy for diabetes management were randomized to receive add-on therapy with either placebo (N = 567) or bexagliflozin 20 mg once daily (N = 1,132) for a minimum duration of 52 weeks (median duration 2.4 years). The most common adverse reactions observed in this trial were generally consistent with other trials of bexagliflozin tablets in adults with type 2 diabetes mellitus (see Table 1 ) . Other Adverse Reactions Lower Limb Amputations An increased incidence of non-traumatic lower limb amputations occurred in bexagliflozin-treated patients compared to placebo-treated patients in a trial (Trial 6) that evaluated adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD. Patients in this trial were followed for a median duration of 2.4 years. The lower limb amputation data are shown in Table 2 . Table 2. Non-traumatic Lower Limb Amputation in Adults with Type 2 Diabetes Mellitus who had either Established Cardiovascular Disease or were at Risk for Cardiovascular Disease (Trial 6 ) Placebo N = 567 Bexagliflozin N = 1,132 Patients with an amputation, n (%) 7 (1.2%) 23 (2.0%) Total amputations 13 25 Amputation incidence rate (per 1,000 patient-years) 5.1 8.3 Hazard Ratio (95% CI) - 1.64 (0.70, 3.82) Note: Incidence is based on the number of patients with at least one amputation, and not the total number of amputation events. A patient’s follow-up is calculated from Day 1 to the first amputation event date. Some patients had more than one amputation. Volume Depletion In a trial of adults with type 2 diabetes mellitus and moderate renal impairment (Trial 5), adverse reactions related to volume depletion (e.g., dehydration, dizziness, dizziness postural, vertigo, vertigo positional, presyncope, hypotension, and orthostatic hypotension) were reported in 3.9% and 8.9% of patients treated with placebo and bexagliflozin tablets, respectively. Genital Mycotic Infections In a pool of three placebo-controlled clinical trials (12-week dose ranging trial and Trials 1 and 2), the incidence of female genital mycotic infections occurred in 0% and 5.6% of females treated with placebo and bexagliflozin tablets, respectively (see Table 1 ). In the same pool of trials, male genital mycotic infections occurred in 1.4% and 2.2% of males treated with placebo and bexagliflozin tablets, respectively (see Table 1 ). In a trial that enrolled adults with type 2 diabetes mellitus and moderate renal impairment (Trial 5), 0% and 9.2% of female patients treated with placebo and bexagliflozin tablets, respectively, had a genital mycotic infection. In a trial that enrolled adults with type 2 diabetes mellitus who had either established CVD or were at increased risk for CVD (Trial 6), 2.8% and 9.0% of patients treated with placebo and bexagliflozin tablets, respectively, had at least one event of genital mycotic infection. In the same trial, genital mycotic infections that caused drug discontinuation were reported in 0% and 1.2% of patients treated with placebo and bexagliflozin tablets, respectively. Balanoposthitis was reported in 0% and 2.9% of male patients, and phimosis was reported in 0.3% and 0.5% of male patients treated with placebo and bexagliflozin tablets, respecti